[Background] Antibody-mediated chronic rejection is one of the main obstacles to achieving long-term success of transplant. We demonstrated that alemtuzumab induction with rapamycin maintenance therapy is associated with an increased incidence of antibody-mediated rejection in human patients. The role that rapamycin plays in homeostatic dysregulation following T cell depletion and the recovery effect of CTLA-4 Ig are the subjects of this study.
[Methods] We transplanted C56BL/6 hearts to human CD52 transgenic CBA mice. Alemtuzumab (10Μg/dose) was given on days -2, -1, +2, and +4 of transplantation with or without rapamycin (75Μg/kg for 21 days, i.p.). CTLA-4 Ig (250Μg/dose) was treated on day 0, +2, +4, and +6 of transplantation. Donor specific antibodies (DSA) were measured with flow cytometry. Neo-intimal hyperplasia and diseased vessels were measured by morphometric analysis for quantifying chronic rejection at 100 days after heart transplantation.
[Results] Graft survival was not different between the two groups, alemtuzumab alone and alemtuzumab/rapamycin. However, recipients treated with alemtuzumab/rapamycin showed elevated DSA titer at post-transplant day 100 (Fold increase, 8.41±1.98 vs. 2.36±0.45; p<0.01) compared to alemtuzumab alone. Moreover, combined alemtuzumab/rapamycin treatment was associated with an increased severity of chronic rejection measured by neo-intimal hyperplasia (% occlusion, 60.63±18.05% vs. 21.78±6.38%; p<0.05) and vasculopathy (% affected, 74.20±15.76 vs. 27.53±7.98; p<0.05) compared to alemtuzumab alone. Interestingly, decreased number of T regulatory cells was observed in the spleens during treatment of combined treatment at 3 weeks after transplantation. A trend of increased IgG1 isotype was observed in these recipients. Finally, additional CTLA-4 Ig treatment showed a trend of decreased (DSA) and severity of chronic rejection compared to alemtuzuamb/rapamycin treatment.
[Conclusion] This study showed that early rapamycin treatment during homeostatic T cell repopulation promotes DSA, chronic rejection via interrupting homeostasis of regulatory T cells. These data suggest a possibility of connections between DSA production and regulatory T cells in the early time point of homeostatic proliferation, and possibility of combined CTLA-4 Ig treatment for preventing chronic rejection development.
To cite this abstract in AMA style:Oh B, Kwun J, Ruhil R, Gibby A, Page E, III AFarris, Kirk A, Iwakoshi N, Knechtle S. Rapamycin Enhances Early Alloantibody Production by Hampering the Homeostatic Proliferation of Regulatory T Cells [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/rapamycin-enhances-early-alloantibody-production-by-hampering-the-homeostatic-proliferation-of-regulatory-t-cells/. Accessed October 26, 2020.
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